Thiazines

ABSTRACT

ANTI-INFLAMMATORY AGENTS OF THE FORMULA   (B-ALK-N&lt;(-CO-CH(-Z-R)-(Y)N-C(=)-A=A-A=A-C(=)-))-(X)M   WHERE BOTH C&#39;&#39;S ARE JOINED   ALK MAY BE A STRAIGHT OR BRANCHED CARBON CHAIN OF UP TO 6 CARBON ATOMS; AND B MAY BE A BASIC NITROGEN-CONTAINING RADICAL; AND PHARMACEUTICALLY ACCEPTABLE ACID-ADDITION SALTS THEREOF; N OXIDES AND PHARMACEUTICALLY ACCEPTABLE ACID-ADDITION SALTS THEREOF, AND QUATERNARY AMMONIUM SALTS THEREOF.   &gt;C(-R&#39;&#39;)-OOC-R   WHEREIN R&#39;&#39; IS HYDROGEN, VINYL, ALLYL OR R, OR   -CO-, -C(-OH)(-R&#39;&#39;)-   WHEREIN X MAY BE HYDROGEN, HALOGEN, ALKYL, HALOALKYL, HALOALKOXY, HALOALKYLTHIO, ALKOXY, HYDROXY, ALKYLTHIO, NITRO, ALKYLSULFONYL, AMINO, ALKANOYLAMINO OR MONO- OR DIALKYLAMINO WHEREIN ANY OF THE FOREGOING ALKYL OR SUBSTITUTED ALKYL RADICALS CONTAIN UP TO 8 CARBON ATOMS; M MAY BE 0, 1, 2, 3 OR 4; EACH A MAY BE CARBON, BUT ONE A MAY BE NITROGEN IN ANY POSITION PROVIDED N IS 1; Y MAY BE SULFUR, SULFOXIDE, SULFONYL, OR OXYGEN; N MAY BE 0 TO 1; R MAY BE A STRAIGHT OR BRANCHED ALKYL OF UP TO 8-CARBON ATOMS CYCLOALKL OF FROM 3 TO 8 CARBON ATOMS, PHENYL XSUBSTITUTED PHENYL, PYRIDYL, THIENYL, FURYL, NAPHTHYL, ALKYLPHENYL OR ALKENYLPHENYL WHEREIN THE ALKYL OR ALKENYL RADICAL MAY CONTAIN UP TO 4 CARBON ATOMS EITHER STRAIGHT CHAIN OR BRANCHED; Z MAY BE

United States Patent O "ice 3,767,653 THIAZINES John Krapcho, Somerset, N.J., assignor to E. R. Squibb & Sons, Inc., New York, NY. No Drawing. Filed June 28, 1971, Ser. No. 157,678 Int. Cl. C07d 93/12 US. Cl. 260-243 R 12 Claims ABSTRACT OF THE DISCLOSURE Anti-inflammatory agents of the formula x... ll

aik-B (II) wherein X may be hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, haloalkylthio, alkoxy, hydroxy, alkylthio, nitro, alkylsulfonyl, amino, alkanoylamino or monoor dialkylamino wherein any of the foregoing alkyl or substituted alkyl radicals contain up to 8 carbon atoms; m may be 0, l, 2, 3 or 4; each A may be carbon, but one A may be nitrogen in any position provided 11 is 1; Y may be sulfur, sulfoxide, sulfonyl, or oxygen; 12 may be 0 to 1; R may be a straight or branched alkyl of up to 8 carbon atoms cycloalkyl of from 3 to 8 carbon atoms, phenyl X- substituted phenyl, pyridyl, thienyl, furyl, naphthyl, alkylphenyl or alkenylphenyl wherein the alkyl or alkenyl radical may contain up to 4 carbon atoms either straight chain or branched; Z may be wherein R is hydrogen, vinyl, allyl or R, or

0 0 iiR alk may be a straight or branched carbon chain of up to 6 carbon atoms; and B may be a basic nitrogen-containing radical; and pharmaceutically acceptable acid-addition salts thereof; N oxides and pharmaceutically acceptable acid-addition salts thereof, and quaternary ammonium salts thereof.

SUMMARY OF THE INVENTION Anti-inflammatory agents of the formula Xm+ H ink-B (II) wherein X may be hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, haloalkylthio, alkoxy, hydroxy, alkylthio, nitro alkylsulfonyl, amino, alkanoylamino or monoor dialkylamino wherein any of the foregoing alkyl or substituted alkyl radicals contain up to 8 carbon atoms; m may be 0, l, 2, 3 or 4; each A may be carbon, but one A may be nitrogen in any position provided It is 1; Y may be sulfur, sulfoxide, sulfonyl, or oxygen; n may be 0 or 1; R may be a straight or branched alkyl of up to 8 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenyl, X-substituted phenyl, pyridyl, thienyl, furyl, naphthyl,

3,767,653 Patented Oct. 23, 1973 alkylphenyl or alkenylphenyl wherein the alkyl or alkenyl radical may contain up to 4 carbon atoms either straight chain or branched; Z may be OH 0:0, o

wherein R is hydrogen, vinyl, allyl or R, or

0 0 i l R alk may be a straight or branched carbon chain of up to 6 carbon atoms; and B may be a basic nitrogen-containing radical; and pharmaceutically acceptable acid-addition salts thereof; N-oxides and pharmaceutically acceptable acid-addition salts thereof, and quaternary ammonium salts thereof.

OBJECTS OF THE INVENTION It is an object of the present invention to provide new compounds having anti-inflammatory activity. Another object is to provide a method for the preparation of these compounds. A further object is to provide dosage forms containing the compounds of the invention. Yet another object is to provide a method for treating inflammatory conditions by administering the compounds of the invention. These and other objects of the present invention will be apparent from the following description.

DETAILED DESCRIPTION The compounds of the present invention may be prepared according to the following reaction sequence wherein X, m, A, Y, n, alk, B, and R are as defined previously:

alk-B l 1) condensing agent 2) R-aeylatlng agent alk-B As condensing agent there may be employed such materials as, e.g., NaH, NaOCH butyl Li, or K-t-butoxide.

The acylating agent may be an acyl halide,

o Bil-hal, or an ester of the formula 'wherein R is as defined previously, hal is halogen and R" is an organic radical, preferably a lower alkyl radical, e.g., methyl.

The acylation of the compound of Formula I to form the corresponding compound of Formula IIa takes place in a polar solvent such as, e.g., dimethylsulfoxide, tetrahydrofuran or ethyl acetate in the presence of a condensing agent. The reaction is exothermic and cooling may be necessary to keep the reaction below about 30. When the reaction is completed, the mixture is heated to mod erately elevated temperature of from about 50 to about 75 for from about 0.5 hour to about 4 hours, preferably from about 1.5 hours to about 2.5 hours. The pH of the resulting solution is then adjusted to from about 8.5 to about 9.5 to yield the compound of Formula Ha as a precipitate which is then purified by solvent and aqueous extraction and crystallization.

Compounds of Formula 1121 may be converted to the corresponding secondary alcohol (IIb) by treatment with a reducing agent such as, for example, NaBH or LiAlH Na isopropoxide or catalytically using, e.g., Pd on carbon, while the corresponding tertiary alcohol (He) may be obtained by reaction of the compound of Formula Hat with a Grignard reagent, RMghal, wherein R and hal are as previously defined.

The hydroxyl group of the compounds of Formula Ilb and He may be esterified, for example, by use of an acid anhydride or an acyl halide of alkanoic acids of the formula 0 O 120 or RC% OH hal wherein R and hal are as previously defined.

Compounds of Formula 11a, 11b or IIc which are derived from the foregoing compounds of Formula I will be further designated as Ila-l, Ila-2, Ila-3, etc., wherein the arabic numeral indicates the type of compound of Formula I from which it may be prepared.

(A) When Y is sulfur and each A is carbon, the compounds of Formula 11 may be prepared by reacting an o-aminobenzenethiol or an X -substituted o-arninobenzenethiol of Formula ill with a halo-acetic acid, and reacting the resulting thiazinone of Formula IV with a haloalkylene-B compound to yield a compound of Formula 1-1. The latter compound is then treated with a condensing agent and with an acylating agent to yield the corresponding compound of Formula IIa-l. The compound of Formula Ila-1 may be converted to the corresponding compound of Formula IE) or Hc as described above.

S H hal-CH CO2H CH,

-NH: \N/

III Iv hallalkylene-B s it 1) condensing CH R agent CH, X... (5

2) R-imylating =0 \N/ agent \N/ elk-B zLlloB Examples of suitable o-arninobenzenethiols which may be used as starting material in the foregoing reaction sequence are the following:

2-aminobenzenethio1; 4-fluoro-Z-aminobenzenethiol; S-fluoro-Z-aminobenzenethiol;

3,5 ,6-trifluoro-Z-aminobenzenethiol; 3,4,5 ,G-tetrafluoro-Z-aminobenzenethiol; 4-chloro-Z-aminobenzenethiol;

5 -chloro-2-aminobenzenthiol; 6-chloro-2-aminobenzenethiol; 5-bromo-2-aminobenzenethiol; 5-methyl-Z-aminobenzenethiol; 6-methyl-2-aminobenzenethiol; 5-ethyl-2-aminobenzenethiol;

S-n-propyl-Z-aminobenzenethiol;

5 -n-hexy1-2-aminobenzenethiol; 3-hydroXy-2-aminobenzenethiol; 5-methoxy-2-aminobenzenethiol;

3 ,4-dimethoxy-2-aminobenzenethiol; 5-ethoxy-Z-aminobenzenethiol; 5-n-propoXy-2-aminobenzenetl1iol; S-n-hexyloxy-Z-aminobenzenethiol; 4-ethylthio-2-aminobenzenethiol;

4- (trifluoromethyl) -2-aminobenzenethiol;

5- (trifluoromethyl -2-aminobenzenethiol;

6- (trifluoromethyl) -2-aminobenzenethiol;

5- (trifluoromethoxy) -2-aminobenzenethiol;

4 (trifluoromethylmercapto -2a.minobenzenethiol; 5-trifluoromethylmercapto) -2-aminobenzenethiol; S-nitro-2-aminobenzenethiol; 6-nitro-2-aminobenzenethiol; 2,4-diamino-S-methylthiophenol;

5 -dimethylamino-2-aminobenzenethiol; 4-methylsulfonyl-2-aminobenzenethiol (B) When Y is oxygen, and each A is carbon, the compounds of Formula II may be prepared by reacting an o-nitrophenol or an X -substituted o-nitrophenol of Formula V with a haloacetic acid followed by reduction of the nitro group to an amino group. Cyclization takes place spontaneously following reduction to yield a compound of Formula VI. Reaction of the oxazinone compound of Formula VI with a haloalkylene-B compound yields a compound of Formula 1-2. The latter compound is then treated with a condensing agent and with an acylating agent to yield the corresponding compound of Formula Ila-2. The compound of Formula IIa-2 may be converted to the corresponding compound of Formula IIb or IIc as described previously.

OH 1 hal-cHzCO H on, 2 a t m I: 0

re uc ion I V VI H hallalkylene-B 1) Condensing C-IEI R agent CH; Xm (IJ Xm I :0 2) R-acylat1ng C: agent I a lk-B alk-B Ila-2 I-2 Suitable o-nitrophenols which may be used as starting material in the foregoing reaction sequence are the following:

2-nitropheno1; 2-nitro-4-chlorophenol; 2-nitro-4,6-dichlorophenol; 2-nitro-3,4,5,6-tetrachlorophenol; 2-nitro-4-bromophenol;

2-nitro-3 ,S-dibromophenol; Z-nitro-S-trifiuoromethoxyphenol; 2-nitro-4-ethylthiophenol; 2-nitro-4,6-dibromophenol; 2,4-dinitrophenol;

2,5 -dinitrophenol; 2,6-dinitrophenol; 2,4-dinitro-6-chlorophenol; 2,S-dinitr0-4-chlorophenol; 2,6-dinitr0-4-chlorophenol; 2,4-dinitro-6-bromophenol; 2,6-dinitro-4-bromophenol; 2,4,6-trinitrophenol;

6 2-nitro-6-methylphenol; 2-nitro-4-bromo-G-methylphenol; 2,4-dinitro-6-rnethylphenol; 2-nitro-3-methylphenol; 2-nitro-4-methylphenol; 2-nitro-5-methylphenol; 2,4,6-trinitro-5 -methy1pheno1; 2-nitro-4-methyl-6-chlorophenol; 2-nitro-4-methy1-6-bromophenol; 2,5-dinitro-4-methylphenol; 2,6-dinitro-4-methylphenol; 2-nitro-4,S-dimethylphenol; 2-nitro-4,6-dimethylphenol; 2-nitro-3,4,6-trimethy1phenol; 2,4-dinitro-3-i-propyl-6-methylphenol; 2-nitro-4-methylaminophenol; 2-nitro-5-chlorophenol; 2-nitro-5-fluorophenol; 2-nitro-4-fluorophenol; 2-nitro-5-bromophenol; Z-nitro-4-methylsulfonylphenol; 2-nitro-5-dimethylaminophenol; 2-nitro-5-ethylphenol; 2-nitro-5-n-hexylphenol; 2-m'tro-5-methoxyphenol; 2-nitro-5-ethoxyphenol; 2-nitro-S-n-hexyloxyphenol; 2-nitro-5- (trifluoromethyl phenol.

(C) When n is 0, the compounds of Formula II may be prepared by reacting an X -substituted dihydroindolone of Formula VII with a haloalkylene-B compound to yield a compound of Formula L3. The latter compound is then treated with a condensing agent and with an acylating agent to yield the corresponding compound of Formula Ila-3 which in turn may be converted to the corresponding compound of Formula IIb or as described previously.

X hal-alkylene-B m o=0 o=o I H aIlk-B VII 1-3 1) condensing agent I// 2) R-acylatmg agent R xm C=O I alk-B Ila-3 The dihydroindolone may be prepared by reacting aniline or an X -substituted aniline with a-chloroacetic acid, and treating the resulting amide with AlCl (Friedel-Crafts reaction) to eifect ring closure. Examples of suitable sub stituted anilines which may be used as starting materials in the foregoing reaction sequence are the following:

Z-methylaniline (o-toluidine), 3-methylani1ine (m-toluidine), 4-methylaniline (p-toluidine), 2,3-dimethylaniline, 2,4-dimethylaniline, 2,5-dimethylaniline, 3,4-dimethylaniline, 3,5-dimethylaniline, Z-ethylaniline, 2-isopropylaniline, 4-n-butylaniline,

4-t-butylaniline,

Z-fluoroaniline,

3-fluoroaniline,

4-fiuoroaniline,

2-chlor0aniline,

3-chloroaniline,

4-chloroaniline,

2-bromoaniline,

3-bromoani1ine,

4-bromoaniline,

2-iodoanjline,

3-iodoaniline,

4-iodoaniline, 2,3-dichloroaniline, 2,4-dichloroaniline, 2,5-dichloroaniline, 3,4-dichloroaniline, 3,5-dichloroaniline, 2,3-dibromoaniline, 3,4-dihromoaniline,

3,5 -dibromoaniline, 2,4-diiodoaniline, 2-methyl-3-chloroaniline, 2-methyl-4-chloroaniline, 2-methyl-4-bromoaniline, 2-chloro-4-methylaniline, 3-chloro-4-methylaniline, 2-bromo-4-methylaniline, 2-methoxyaniline, 4-methoxyaniline, 3,5-dimethoxyaniline, 4-ethoxyaniline, 2-chloro-5-methoxy aniline, 2-nitroaniline,

3-nitroaniline,

4-nitroaniline,

2,4-dinitroaniline, 2-nitro-4-chloroaniline, 3-nitro-4-chloroaniline, 2-chloro-4-nitroaniline, 2-chloro-5-nitroaniline, 2-bromo-4-nitroaniline, 2-nitro-4,S-dichloroaniline, 2,4-dim'tro-S-chloroaniline, 2,4-dinitro-S-bromoaniline, 2,4-dinitro-B-methylaniline, 2,4-dinitro-S-methylaniline, 4-dimethy1aminoaniline, 3-trifluoromethylaniline, 2-trifiuoromethyl-4-nitroaniline, 2-nitro-4-trifluoromethylaniline, Z-methoxy- I-methylmercaptoaniline, Z-methylmercapto-4-methoxyaniline, 4- n-butylsulfonyl -2-aminoanisole, 4- (ethylsulfonyl) -2-aminoanisole, Z-ethylsulfonyl-S-trifluoromethylaniline, and 2-methoXy-4-ethylsulfonylaniline.

(D) When Y is sulfur and one A may be nitrogen, the compounds of Formula II may be prepared by substituting for the thiazinone in paragraph A above one of the following compounds or an X -substituted derivative thereof:

Type of 1-4 compound of Formula I: 1 l-pyrido[2,3-b][1,4]-thiazin-2(3 Ij )-one.

1-5 1-pyrido[3,4-b] [l,4]-thiazin-2(3g)-one. 1-6 1 I1-pyrido[4,3-b] [1,41-thiazin-2 3E)-one. 1-7 l-pyrido[3,2-b][1,4]-thiazin-2(3g)-one.

(B) When Y is oxygen and one A may be nitrogen, the compounds of Formula II may be prepared by substituting for the oxazinone in paragraph B above one of the following compounds or an X -substituted derivative thereof:

Type of compound of Formula I:

I-Il 2g-pyrido[3,2-b] l,4]-oxazin-3 (4 I1)-one. I-8 2g-pyrido[2,3-b] [1,41-oxazin-3 (4E) -one. 1-9 2I :I-pyrido{3,4-b] [1,41-oxazin-3 (4I I) -one. 1-1 0 2g-pyrido[4,3-b] [1,4]-oxazin-3 (43) -one.

The pyridyl compounds of Formula 1-8, 1-9, 1-10 and 1-11 may be prepared in an analagous manner to the benzoxazines of Formula 1-2 by starting from a hydroxy nitropyridine or an X -substituted hydroxynitropyridine in place of an o-nitrophenol.

(F) When Y is sulfur, the sulfoxide or sulfonyl compounds of Formula II may be prepared by oxidizing the bivalent sulfur to the corresponding sulfoxide or sulfonyl. The techniques for such oxidations involve the use of H 0 and KMnOl respectively, and are well known in the art. Alternatively, there may be employed a chloroform solution containing m-chloroperbenzoic acid. The sulfoxide of a compound of Formula Ha may be obtained by treating a compound of Formula Ha for from about 2 to about 24 hours at room temperature with one equivalent of m-chloroperbenzoic acid; the sulfone of a compound of Formula He may be obtained by treating one of the bivalent sulfur compounds with two equivalents of m-chloroperbenzoic acid for the same time at room temperature, or for a shorter time with slight heating.

0 o o A s ll A Q l A/ \Q( \R H202 A/ \G \R Jeni-C) (L H xm+ I H A =0 A c=o \A/\N/ \A silk-13 a'lk-B Ila IIa-sultoxide 7 A s A/ xmlg lin A =0 ailk-B IIa-sulionyl The alkyl radical alk may be a straight or branched carbon chain of up to 6 carbon atoms. Examples of such radicals are the following: methyl, ethyl, n-propyl, ipropyl, n-butyl, i-butyl, t-butyl, n-pentyl, Z-methyl-n-butyl, neopentyl, n-hexyl, Z-methyI-n-pentyl, 3-methyl-n-pentyl, 2,2-dimethyl-n-butyl, and 2,3-dimethyl-n-butyl.

Among the suitable radicals represented by the basic nitrogen containing radical B are the following:

amino;

(lower alkyl)amino (e.g., N-methylamino);

di(lower alkyl)amino (e.g., N,N-dimethylamino);

(hydroxy lower alkyl)amino',

(hydroxy lower alkyl) (lower alkyl)amino (e.g., N-2- hydroxyethyl-N-methylamino di(hydroxy lower alkyl)amino;

phenyl(lower alkyl) amino;

N-phenyl lower alkyl (lower alkyl)amino; and saturated to 7-membered monocyclic heterocyclic radicals of less than twelve carbon atoms, as exemplified by:

piperidino;

(lower alkyl)piperidino;

di(lower alky1)piperidino;

(lower alkoxy)piperidino;

homopiperidino;

2-, 3-, or 4-piperidyl;

2-, 3-, or 4-(N-lower alkylpiperidyl);

pyrrolidino;

(lower alkyl)pyrrolidino;

di(lower alkyl)pyrrolidino;

(lower alkoxy) pyrrolidino;

2- or 3-pyrrolidyl;

2- or 3-(N-lower alkyl pyrrolidyl);

morpholino;

(lower alkyl)morpholino;

di(lower alkyl)morpholino;

(lower alkoxy)morpholino;

thiamorpholino;

(lower alkyl)thiamorpholino;

di(lower alkyl)thiamorpholino;

(lower alkoxy)thiamorpholino;

piperazino;

4-R-substituted piperazino (e.g., N -ethylpiperazino,

N -phenylpiperazino, and so forth);

di(lower alkyl)amino-(lowcr alkyl)piperazyl (e.g.,

N -dimethylaminoethylpiperazino) (lower alkyl)-piperazino (e.g., N -rnethylpiperazino);

di(lower alkyl)piperazino;

(lower alkoxy) piperazino;

homopiperazino;

and 4-R-substituted homopiperazino (e.g., N -benzylhomopiperidino.

The lower alkyl and substituted lower alkyl radicals in the foregoing basic nitrogen containing radicals, B, may contain up to 6 carbon atoms.

The compounds of the invention may be obtained as mixtures of diasteroisomeric compounds when they contain more than one asymmetric atom. Such mixtures of racemates can then be separated into individual racemic compounds.

As to the salts, those coming within the purview of this invention include the acid-addition salts, particularly the pharmaceutically acceptable acid-addition salts, N-oxides and pharmaceutically acceptable acid-addition salts of N-oxides, and pharmaceutically acceptable quaternary ammonium salts. Acids useful for preparing these acidaddition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic acid, theophylline, 8-chlorotheophylline, p-aminobenzoic, p-acetamidobenzoic, nicotinic, methanesulfonic or cyclohexanesulfamic.

The N-oxide may be formed by dissolving the free base of Formula II in a solvent inert to hydrogen peroxide, e.g., ethanol or chloroform, adding excess (on a molar basis) hydrogen peroxide, and allowing the mixture to stand at room temperature for several hours. An acidaddition salt of the N-oxide may be formed by addition of the desired acid, for example, those mentioned above.

The quaternary ammonium salts include those formed with alkyl halides (e.g., methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide), benzyl halides (e.g., benzyl chloride) and dilower alkyl sulfates (e.g., dimethyl sulfate).

The compounds of this invention are useful as antiinfiammatory agents and are efiective in the prevention and inhibition of granuloma tissuse formation in warm blooded animals, for example in a manner similar to phenylbutazone or indomethacin. They may be used to decrease joint swelling tenderness, pain and stifiness in mammalian species, e.g., in conditions such as rheumatoid arthritis. The compounds of this invention or a physiologically acceptable acid-addition salt thereof may be compounded according to accepted pharmaceutical practice for admiinstration orally or by injection. Suitable oral dosage forms are tablets, capsules, elixirs, suppositories, or powders, while solutions or suspensions are suitable for injection. The quantity administered may be from about 25 mg. to about 2 gm. per day, and preferably from about 50 mg. to about 200 mg. per day.

The following examples illustrate the invention without, however, limiting the same thereto. All temperatures given are in degrees centigrade unless otherwise stated.

EXAMPLE 1 (A) 4- [2- (dimethylamino ethyl] -2-1,4-benzothiazin- 3(4g)-one.A mixture of 108 g. of 1,4-benzothiazin- 3(4 I1)-one in 650 ml. of DMF is stirred and treated portionwise with 32.5 g. of sodium hydride (50% dispersion) while maintaining the temperature below 50. The solution is then heated to cooled to 25 and treated with 350 ml. of 2.8 N toluene solution of Z-dimethylaminoethyl chloride and 6 g. of sodium iodide. This mixture is heated at 100-105 for 3 hours, cooled, poured into 2 liters of ice-water, and extracted with 500 ml. of ether (three times). The organic phases are combined and extracted with a solution of 120 ml. of concentrated HCl in 500 ml. of water. The aqueous phase is cooled and treated portionwise with 240 g. of -K CO The liberated base is extracted with 500 ml. of ether (three times), the organic phases are combined, dried (Mgs filtered and the solvent evaporated. The residue is fractionated to give 103.5 g. of colorless product; B.P. 146-149 (0.2 mm.).

(B) 2-benzoyl 4 [2-(dimethylamino)ethyl]-2E-1,4- benzothiazin-3(4E)-one, h'ydrochloride.A solution of 24 g. of the product from part (A) and 25 ml. of methyl benzoate in 100 ml. of dimethylsulfoxide (DMSO) is stirred and treated portionwise with 10 g. of 50% NaH. About 10 minutes after the completion of the addition, a vigorous reaction occurs, accompanied by considerable foaming and a moderate temperature rise. (The mixture is cooled intermittently to keep the temperature below 30.) When the reaction has subsided, the mixture is heated at 60-65 for 2 hours, kept overnight at room temperature, and poured with stirring into 600 ml. of ice-water. The pH of the resulting solution is adjusted to 9.0 with 10% acetic acid to give a gummy precipitate. The latter is extracted with chloroform (4X 200 ml.), dried (MgSO and the solvent evaporated. The residue (ca. 50 g.) is taken up in 500 ml. of ether and extracted with a cold solution of 10 ml. of concentrated HCl in 120 ml. of water, followed by 50 ml. of water. The combined aqueous layers are washed with ether, cooled, and basified with 20 g. of K 00 The liberated base is extracted with ether (4X 200 ml.), dried (MgSO and the solvent evaporated to give 34.4 g. of solid, M.P. 87 (s. 80). Crystallization from a mixture of 70 ml. of benzene and 70 ml. of hexane gives 27 g. of creamcolored base; M.P. 8890 (s. 80). The analytical sample is recrystallized from acetonitrile; M.P. 105407".

A cooled solution of the base (13 g.) in 400 m1. of ether is treated with ml. of ether containing 7 ml. of 5.9 N alcoholic HCl to precipitate the hydrochloride as a pale yellow solid. After cooling for 3 hours, the material is collected under nitrogen, Washed with ether, and dried in vacuo; wt., 13.2 g. (72%); M.P. ISO-152 (foam); s., 74. Crystallization from 100 ml. of hot acetonitrile gives 9.3 g. of colorless product; M.P. 177- 179.

EXAMPLE 2 (A) 4-[3-(dimethylamino)propyl]2g 1,4 benzothiazin-3(4 Ii)-one.The title product is prepared by react- 1 1 ing sixty grams (0.36 mole) of 1,4-benzothiazin-3(4 ]F I one in 360 ml. of DMF with 18 g. (0.37 mole) of 50% NaH, 260 ml. (0.55 mole) of a 2.1 N toluene solution of S-dimethylaminopropyl chloride, and 4 g. of sodium iodide according to the procedure described in Example 1, part (A); yield, 57.7 g.; B.P.. l57l60/0.2 mm.

(B) 2 benzoyl-4-[3-(dimethylamino)propyl] -2-1,4- benzothiazin 3 (4g) one, hydrochloride.-The product from part (A) (25 g.; 0.1 mole) is reacted with 25 ml. (0.2 mole) of methyl benzoate and 10 g. (0.2 mole) of 50% NaH in 100 ml. of DMSO according to the procedure described in Example 1, part (B). The crude solid base (36 g.) is crystallized from 50 ml. of acetonitrile to give 24.2 g. of pale yellow solid; M.P. 88-90".

A cooled solution of 12 g. of base in 300 ml. of ether is treated with 100 ml. of ether containing 4.5 ml. of 7.8 N alcoholic HCl to precipitate the solid hydrochloride. After standing in the cold overnight, the latter is collected under nitrogen, Washed with ether, and dried in vacuo, wt. 13.4 g. (69%); M.P. 108-110 (foaming), s. 94. The material is dissolved in 200 ml. of chloroform, Darco-treated, and the solvent evaporated to give a foamy residue which was crystallized from 100 ml. of acetone. The material dissolves readily, then a crystalline solid rapidly separates. After cooling overnight, the yield of colorless product is 9.2 g.; M.P. 176-178.

Example 3.4 [3 dimethylamino)propyl]-2-pivaloyl- 2g-1,4-benzothiazin-3 (431) -one, hydrochloride 4 [3 (dimethylamino)propyl]-2g-l,4-benzothiazin- 3(4)-one (2.5 g.) prepared as described in Example 2, part (A) is reacted with 21 g. of methyl pivalate and 9 g. of 50% NaH in 100 ml. of DMSO as described in Example 1, part (B). There is only a slight temperature rise (31) and no vigorous foaming. The mixture is stirred at 70-75 for 3 hours, cooled, poured into 600 ml. of icewater, neutralized to pH 8 with AcOH, and extracted with ether (4X 200 ml.). The combined extracts are dried (M so, and the solvent evaporated to give 24 g. of oil. The latter is taken up in ether and extracted with a cool solution of 15 ml. of concentrated HCl in 250 ml. of H followed by 50 ml. of H 0. The combined aqueous layers are cooled, basified with 30 g. of K CO extracted with ether (3X 150 ml.) and the combined extracts dried (MgSO Evaporation of the ether gives 18 g. of oil.

When a solution of the latter in 70 ml. of hexane is scratched, a crystalline solid separates. After standing in the cold overnight, the base is collected, washed with hexane, and dried; wt., 7.6 g., M.P. 61-63".

A cooled solution of the base (7.4 g.) in 20 ml. of EtOH is treated with 2.8 ml. of 7.7 N alcoholic HCl and diluted to cloudiness with ether (ca. 180 ml.). 0n scratching, the crystalline hydrochloride gradually separates; crude yield after cooling overnight, 6.4 g.; M.P. 148-150 (s., 125 The material is slightly hygroscopic. Crystallization from 50 ml. of CH CN gives 5.8 g. of nearly colorless, non-hygroscopic solid; M.P. 234-236".

Example 4.-4-[3- (dimethylamino)propyl] -2-isonicotinoyl-Zfi-l,4-benzothiazine-3 (451) -one, hydrochloride Twenty-five grams (0.1 mole) of 4-[3-(dimethylamino)propyl 2g-l,4-benzothiazin-3(4g)-one prepared as described in Example 2, part (A) is reacted with 25 ml. of methyl isonicotinate and g. of 50% NaH in 100 ml. of DMSO as described in Example 1, part (B). The vigorous reaction is accompanied by considerable foaming even with ice-cooling.

The syrupy base (12.2 g.) is taken up in 600 ml. of ether, cooled, and treated with 150 ml. of ether containing 4.5 ml. of 7.7 N alc. HCl to precipitate the hydrochloride as a yellow-orange amorphous solid. After cooling for 3 hours, the latter is collected under N washed with ether, and dried in vacuo; wt., 11 g.; M.P. 107-109 (foaming).

12 Example 5.-2 benzoyl 4-[3-(dimethylamino) propyl]- 22 pyrido[3,2-b] [1,4] oxazin 3(4g)-one, hydrochloride (A) 4 [3 (dimethylamino)propyl]-2I -pyrido[3,2- b] 1,4 oxazin-3(4g)-one.-Twenty-five grams (0.17 mole) of 2E-pyrido[3,2-b][1,41-oxazin-3 (4 E l -one are reacted with 8.5 g. (0.18 mole) of 60% NaH, 120 ml. (0.26 mole) of a 2.2 N toluene solution of 3-dimethylaminopropyl chloride and 2 g. of sodium iodide in 170 ml. of DMF as described in Example 1, part (A); yield, 21 g.; B.P. l31-l33/0.2 mm.

(B) 2 benzoyl 4 [3-(dixnethylamino)propylI-ZE- pyrido[3,2-b] [1,4]-oxazin-3(4g) one, hydrochloride- The product from part (A) (16 g.; 0.068 mole) is r a ted with 17 ml. (0.14 mole) of methyl benzoate, and 7 g. (0.14 mole) of 50% NaH in ml. of DMSO as described in Example 1, part (B). After the addition of the NaH, the mixture is warmed to 30 (Warm water bath) to initiate the reaction. The temperature is then kept below 35 by means of intermittent ice-water cooling. The reaction mixture is finally stirred at 70-75 for 3 hours and kept overnight at room temperature. The yield of oily base is 22.8 g.

A solution of the base (22.5 g.) in 600 ml. of ether is treated with ml. of ether containing 9.2 ml. of 7.3 N alcoholic HCl to precipitate the hydrochloride as an oil which gradually crystallizes on seeding (seeds obtained from acetonitrile), rubbing, and cooling; crude yield, 20 g.; M.P. 164-169". Crystallization from 70 ml. of acetonitrile gives 13.7 g. of pale yellow material; M.P. 178-180".

EXAMPLE 6 (A) l [3 (dimethylamino)propyl] 1 I I -pyrido- [2,3-b][1,4]thiazin-2-(3g)-one.A 50% oil dispersion of NaH (7.8 g.; 0.16 mole) is added to a stirred suspension of 26 g. (0.16 mole) in 1E-pyrido[2,3-b][1,4]- thianzin-2(3 I-l)-one in 525 ml. of toluene and the mixture gradually warmed, eifervescence occurs at about 90. After heating to reflux for 45 minutes, the mixture is cooled to 30", treated with ml. (0.22 mole) of a 1.8 N. toluene solution of 3-dimethylaminopropyl chloride and refluxed for 4 hours. After standing overnight, the mixture is worked up as described in Example 1, part (A), to give 23 g. of crude base. This is combined with 0 g. of base from an earlier experiment and distilled; yield, 27.3 g.; B.P. l66-169/0.2 mm.

(B) 3 benzoyl 1 [B-(dimethylamino)propyl]-1I pyrido[2,3-b][l,4]thiazin-2(3g) one, hydrochloride.- The product from part (A) (15 g.; 0.06 mole) is reacted with 15 ml. (0.12 mole) of methyl benzoate and 6.1 g. (1.13 mole) of 50% NaH in 65 ml. of DMSO as described in Example 1, part (B). The yield of oily base is 23.8 g.

A solution of the base in 400 ml. of ether is treated with 200 ml. of ether containing 8.4 ml. of 7.15 N alcoholic HCl to precipitate the solid hydrochloride; crude yield, 22 g.; M.P. 126-130" (foaming); s. 119, The material is crystallized from 50 ml. of CH CN to give 16 g. of pale yellow solid; M.P. -188 (dec.).

Following recrystallization from 100 ml. of CH CN, the cream-colored material weighs 11.7 g.; M.P. 192 (dec.).

Example 7.-4- [2- (dimethylamino) ethyl] -2- (a-hydroxybenzyl -2g-1 ,4-benzothiazin-3 (4g) -one, hydrochloride The free base from Example 1 (13.3 g.) is reacted with 4 g. of sodium borohydride in 160' ml. of methanol. The viscous product (11.2 g.) is triturated with 40 ml. of boiling acetonitrile and cooled to give 5 g. of base; M.P. 151-153 The base (4.9 g.) is dissolved in a warm mixture of 15 ml. of chloroform and 15 ml. of methanol, cooled,

13 treated with 2.5 ml. of 5.9 N alcoholic HCl, and diluted with ether to precipitate the hydrochloride as a gum which crystallizes on rubbing and cooling; crude yield, 5.0 g.; M.P. 204-206. Following crystallization from a mixture of 25 ml. of warm methanol and 50 ml. of ether, the colorless material weighs 4.6 g.; M.P. 207-209".

Example 8.4-'[3-(dimethylamino)propyl] 2 (a hydroxybenzyl)-2[ -1,4-benzothiazin-3 (4 1)-one, hydrochloride The free base from Example 2 (12.3 g.) is reacted with 3.6 g. of sodium borohydride in 150 ml. of methanol. The crude syrupy base (12.1 g.) is crystallized from 130 ml. of isopropyl ether to give g. of solid; M.P. 105- 107 (s. 100).

A solution of the base (9.9 g.) in 50 ml. of chloroform is treated with 3.7 ml. of 7.7 N alcoholic HCl and diluted with several volumes of ether to precipitate the hydrochloride as a gum which gradually becomes granular on rubbing and standing in the cold; crude yield, 10.3 g.; M.P. 175-178. Following crystallization from 75 ml. of acetonitrile, the colorless product weighs 7.9 g.; M.P. 182-184".

Examples 9-12 Following the procedure of Example 6 but substituting for 1g-pyrido[2,3-b] [l,4]thiazine-2(3 II)-one the start- Ex. I

15- 2H-pyrido[4,3-b][1,4]oxazin- 3 (4H) -one.

oxazin-3(4H)one.

O X X II S S S C x a 1: EH x 011 x r n R x H =0. X =0 X =0 X x x H Elk-B x alk-B III IV I-l II-I F H H 2- (amino)ethy1 chloride.

H H 01 2-(methylamino)ethyl chloride.

H Br H 2-(diethylamino)ethyl chloride.

H CH3 H 2-methyl-3-(dimethylamino)- propyl chloride.

H H CzH 6-(dimethylamino)hexyl chloride.

H n-CoHu H 2-[bis-N-(2-hydroxyethyl)- amino1ethyl chloride.

H H H 3-(benzylamino)propyl chloride.

SCzH5 H H 3-(N-phenethyl-N-methylamino)- propyl chloride.

H N O: 2-(piperidino)ethyl chloride.

CHaS O: H H 2-(2-methylpiperidino)ethyl chloride.

N H: CH3 H 2-(2, G-dimethylpiperidino) ethyl chloride.

OCH; H H 2-(2-ethoxypiperidino)propyl chloride.

H N (CH3): H

ing material shown in Column I, there is obtained the product shown in Column II:

3-benzoyl-1-IS-(dimethylamino)- p py Ii-py l[ thiazin-2(3H)-one. 3-benzoy1-1-[3-(dimethylamino)- p pv l-lH-py ll thiazin-2(3H)-one. 12..-. 5,7-dibromo-1II-pyrido-[4,3-b]- 3-benzoy1-1-[3,(dimethylamino)- [1,4]thiezin-2-(3H)-one. propyl]-5,7-dibromo-1H- pyrido-[4,3-b][1,41thiazin- 2(3H)-one. Examples 13-18 Following the procedure of Example 5 but substituting for 2 Ii-pyrido[3,2-b][1,4]0xazin-3 (4I )-one the starting material shown in Column I, there is obtained the product shown in Column II:

2-(hexamethy1eneamino) propyl chloride.

Examples 33-46 in Column II according to the procedure of Example I(B), there is obtained the corresponding compound of Formula IIa-l wherein R is the radical indicated in Column III.

I II III Compound of Formula 1-1 of Example Example- R-acylatlng agent R 19 Methylpropionate G3H1 20 Methylacetate CHa 21 Methylhexanoate C5Hn 22 Methyloctanoate --C H 23 Nicotinic acid, methyl ester 38 2A Cyclohexane carboxylic acid,

methyl ester.

39 Pyridine-Z-carboxylic acid, methyl ester. O

40 26 Phenylacetic acid, methyl ester C H: G

41 27 Thiophene-Z-carboxylic acid,

methylester:

42 28 Furane-Z-carboxylic acid, methyl ester.

43 29 Naphthaleue-l-carboxylic acid,

methyl ester. 0

44 30 Naphthalene-2-earboxylic acid,

methyl ester. 0

45 31 o-Toluic acid, methyl ester F H;

46 32 m-Bromobenzoic acid, methyl Br ester.

Example 47.4- [3- (dimethylamino) propyl] -2- tat-propylcinnamoyl -2I -1,4-benzothiazin-3 (411) -one, fumarate salt, hydrate (l: 1: 1)

4 [3 (dimethylamino)propyl]-2E-1,4-benzothiazin- 3(4g)-one (22 g.; 0.088 mole) is reacted with 36 g. (0.18 mole) of methyl a-propylcinnamate and 9 g. (0.18 mole) of NaH (50% oil dispersion) in 100 ml. of DMSO as described in Example 2 to give 33.7 g. of red viscous base. The latter (33.3 g.) is mixed with 9.2 g. of fumaric acid in 70 ml. of MeOI-I and diluted with several volumes of ether to precipitate the fumarate salt as a red oil.

The solvents are decanted and the product rubbed under fresh quantities of ether until it becomes almost completely granular. The yield of tacky orange solid is 35.5 g. (72% The material is then dissolved in 150 ml. of CHCl, and added dropwise to 1.8 liters of vigorously stirred ether to give 25.8 g. (53%) of completely granular, yellow, solid; M.P. l00l02 (s. 80).

A sample of the fumarate is treated with K CO to give the base as a brittle orange solid; M.P. 73-75 (s. 64).

Example 48.-2 benzoyl 4-[2-(dimethylamino)ethyl]- 2 I1-1,4-benzothiazin-3 (4g) -one-1-oxide, hydrochloride By treating the product from Example 1(B) with an equivalent quantity of H 0 in dilute acetic acid and allowing the mixture to stand overnight, the title product is obtained.

Example 49.-2-benzoyl-4- [3 (dimethylamino)propyl]- ZE-lA-benzothiazin-El(4 E1)-one-1-oxide, hydrochloride By treating the product from Example 2(B) with a chloroform solution containing 1 equivalent of m-chloroperbenzoic acid and allowing the mixture to stand for about two hours at room temperature, the title product is obtained.

Example 50.4-[3 (dimethylamino)propyl]-2-pivoloyl- ZE-lA-benzothiazin-3 (4E) -one-1,1-dioxide, hydrochloride By refluxing the product from Example 3 with two equivalents of a chloroform solution of m-chloroperbenzoic acid, the title product is obtained.

Examples 5 1-74 Following the procedure of Example 50 but substituting, respectively, for the product of Example 3, the final product of Examples 6, 10, 12, 19, 22, 24, 25, 28, 29, 30, 31, 33, 35, 39, 40, 42, 44 and 45, there is obtained, respectively, the corresponding sulfonfi.

17 Example 93 .-2-benzoyl-4- [2- (dimethylamino) ethyl] 2g-1,4-benzothiazin-3 (4 I i -one, hydrochloride By heating the sodium salt of o-nitrophenol with an equimolar amount of chloroacetic acid at 60 C. for 2 18 4-, 5- or 6-positions are as indicated in Column I, and substituting for Z-dimethylaminoethyl chloride the chloride of the alk-B radical indicated in Column II, and substituting for methyl benzoate the ester of the formula hours, followed by catalytic reduction of the nitro group 5 by Pd-C (causing spontaneous cyclization), there is obtained benzoxazin-3(4g)-one hydrochloride. Reaction of w 0 the latter with Z-dimethylaminoethyl chloride following the procedure described in Example 1(A) yields 4-[2- dimethylamino)ethyl]-2g-l,4-benzothiazin 3(4I )-one. 10 A solution of the latter compound is reacted with methyl benzoate following the procedure described in Example 1(B) to yield the title product.

whereln R is as lndlcated 1n Column III, there 18 obtained Examples 94-124 the compound of Formula IIa-Z of the following formula Following the procedure of Example 93 but substitutwherein the X alk-B and R substituents are as indicated, ing for o-nitrophenol wherein the substituents in the 3-, respectively, in Columns I, II and III:

0 I o a l R O allk-a h I II III a 4 5 6 alk-B halide R 94 Cl Cl 2-(2-piperldyl)ethyl- CH;

95 Br Br 3-(3- i erid 1) rap 1 pp y p y 96 CH3 2-(4-piperldyDethyl- 01 97 CFa 2-(1-methyl-2-plperldy1)- N01 ethyl.

9B 11-02111 a-(l-methyl-lipiperldyh- N02 propyl.

99 Cl 4-(l-methyl-4-piperidyb- 0H butyl. 100 F 3-(pyrrolidino)propyl OH 101 CH3 2-(2 methylpyrrolidino)- ethyl. OH

102 OCHa 2-(2,5-dimethylpyrrolidino)- ethyl chloride. -@NH,

103 Cl Cl Cl Cl 3-(3-ethoxypyrrolidino)- NH;

p p l 104 Br 2-(2-pyrrolidyl)ethyl H30 105 Br Br 2-(3-pyrrolidyl)ethyl Cl 106 SC2H5 2-(N-methyl-2-pyrrolidyl)- Cl ethyl.

I II III 3 4 5 6 elk-B halide R 107 Br Br 3-(N methyl-3-pyrrolidyl)- Br p py i 108 Br CH; 2-(morplwlino)ethyl 1I3r 109 CH5 3-{2-m0thylmorph0lino)- propyl. -Br

110 C H; 3- (2, 6-dimethylmorph 0- N 03 lino) propyl. l

111 C H; 3-(3-methoxymorpholiuo)- N0 propyl.

112 C H; Cl 2- (thiamorpholino) ethyl 113 CH: Br 3-(piperazi110) ethyl 114 H 3-(4-methylpiperazino)- NH;

p py 115 C1 3-(-cyclohexylpipemzino)- propyl. C H 0 H1- 116 F 3-(4-phenylpiperaz1n0)- 0H propyll 117 S 02011; 2-(4-benzylpiperazinol- 0 C F;

ethyl. l

118 N(C!Ha)z 3-(4-pheuothylpiperazino)- propyl. -C F a 119 C111 3-{4-dimethylaminoothyl)- C H; S piperazinolpropyl. 120 OCJHE 3-(2-mnthylpiperazinw- S 010111 p pv l 121 On-CeHu 3-(2, 6-dimethylpip0raziuo)- propyl' NBC 0 CH;

122 CH; 3-(3methoxypiperaziuo)- NHC H propyl.

123"; CH; 2- (morpholinohthyl N a s):

124 CH3 3-(piperazino)ethyl Example 125.-3-benzoyl-l-{2-(dimethylamino)ethyl] indolin-Z-one, hydrochloride Utilizing the procedure of Example 1 but substituting indolin-Z-one for 1,4-benzothiazin-3(4E)-one in part (A), the title product is prepared.

Example 126.3-benzoyll-[ 2- (dimethylamino) ethyl S-bromoindolin-Z-one, hydrochloride Following the procedure of Example 125 but substituting S-bromoindolin-Z-one for indolin-Z-one, the title prod- 5 net is obtained.

21 Example l27.4- [2- (dimethylamino ethyl] -tx-'methyl-aphenyl-2 I -1,4-benzothiazin-Z-methanol, hydrochloride Interaction of the free base of the product of Example 1 with 1 equivalent of CH MgBr in ether at room temperature forms a Grignard complex which is decomposed with ice water and the ethereal solution dried over anhydrous MgSO filtered and the filtrate treated with anhydrous HCl to yield the title product.

Example l28.2- p-amino) benzoyl-4- 2-( 2,5 -dimethylpyrrolidino)ethyl] 5 hydroxy {Pl-1,4 benzoxazin- 3 (4g) -one, hydrochloride By heating the product of Example 102 in the presence of excess pyridine HCl at 100 C. for 1 hour, the title product is obtained.

Example 129.-2 furyl 4 [2-(piperidino)ethyl]-6- acetylamino 2E 1,4-benzothiazin-3 (4g)-one, hydrochloride By hydrogenating the 6-nitro product of Example 42 in the presence of Pd-C and acrylating the resulting 6- amino compound with 1 mole of acetyl chloride in chloroform, the title product is obtained.

Example 130.2 benzoyl-4-[2-(dimethylamino)ethyl]- 2g-1,4-benzothiazine-3 (4H) -one, methobromide A solution of the free base of Example 1 in acetonitrile is treated with two equivalents of methyl bromide and the solution allowed to stand at room temperature for 8 hours. The solvent is removed to give the product.

Example 131.2 benzoyl-4-[2-(dimethylamino)ethyl]- 2 -1,4-benzothiazine-3 (4E) -one N-oxide A solution of the free base of Example 1 in acetonitrile is treated with two equivalents of H 0 in acetic acid and the solution allowed to stand at room temperature for 8 hours. The solvent is removed to give the product.

What is claimed is:

1. A compound of the formula alk-B wherein X may be hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, haloalkylthio, alkoxy, hydroxy, alkylthio, nitro, alkylsulfonyl, amino, alkanoylamino, or monoor dialkylamino wherein any of the foregoing alkyl or substituted alkyl radicals contain up to 8 carbon atoms; m may be 0, 1, 2, 3 or 4; each A may be carbon, but one A may be nitrogen in any position; Y may be sulfur, sulfoxide, or sulfonyl; R may be a straight or branched alkyl of up to 8 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenyl, X-substituted phenyl, pyridyl, thienyl, furyl, naphthyl, alkylphenyl or alkenylphenyl wherein the alkyl or alkenyl radical may contain up to 4 carbon atoms either straight chain or branched; Z may be wherein R' is hydrogen vinyl, allyl or R, or

alk may be a straight or branched carbon chain of up to 6 carbon atoms; and B may be a basic nitrogen-containing radical selected from the group consisting of amino, (lower alkyl)amino, di(lower alkyl)amino, (hydroxy lower alkyl) (lower alkyl)amino, di(hydroxy lower alkyl) amino, phenyl(lower alkyl)amino, N-phenyl lower alkyl- (lower alkyl)amino, piperidino, (lower alkyl)piperidino, di(lower alkyl) piperidino, (lower alkoxy)piperidino, homopiperidino, 2-, 3- or 4-pyridyl, 2-, 3- or 4-(N-lower alkyl piperidyl), pyrrolidino, (lower alkyl)pyrrolidino, di(lower alkyl)pyrrolidino, (lower alkoxy)pyrrolidino, 2- or 3-pyrrolidyl, 2- or 3-(N-1ower alkyl pyrrolidyl), morpholino, (lower alkyl)morpholino, di(lower alkyl)morpholino, (lower alkoxy)morpholino, thiamorpholino, (lower alkyl) thiamorpholino, di(lower alkyl)thiamorpholino, (lower alkoxy)thiamorpholino, piperazino, 4-R-substituted piperazino, di(lower alkyl)amino(lower alkyl)piperazino, (lower alkyl)piperazino, di(lower alkyl)piperazino, (lower alkoxy)piperazino, homopiperazino, and 4-R-substituted homopiperazino, the lower alkyl and substituted lower alkyl radicals in B having up to 6 carbon atoms; and pharmaceutically acceptable acid-addition salts thereof; N-oxides and pharmaceutically acceptable acid-addition salts thereof, and quaternary ammonium salts thereof.

2. A method for preparing a compound of claim 1 wherein Z is C=O which comprises reacting a compound of the formula alk-B wherein X, m A, Y, alk and B are as defined in claim 1 with a condensing agent selected from the group consisting of NaH, NaOCI-I butyl Li, or K-t-butoxide and an R- acylating agent of the formula l RC-hal or an ester of the .formula wherein R is as defined in claim 1, hal is halogen and R" is a lower alkyl radical.

3. A compound according to claim 1 having the formula A R 0-H wherein X, m, alk, B, Y, R and Z are as defined in claim 1.

4. A compound according to claim 1 having the formula 2 %A Y\ R at I A\ =0 like wherein X, m, A, alk, B, Y, R and Z are as defined in claim 1 provided one A must be nitrogen.

5. A compound according to claim 1 having the name 2 benzoyl 4 [Z-(dimethylamino)ethyl]-2H-1,4-benzothiazin-3 (4;!) -one.

6. A compound according to claim 1 having the name 2 benzoyl 4 [3 (dimethylamino)propyl]-2H-1,4- benzothiazin-3 (4g) -one.

7. A compound according to claim 1 having the name 4 [3 (dimethylamino)propyl]-2-piva1oyl-2 Ii-1,4-benzothiazin-3 (4 I;I -one.

8. A compound according to claim 1 having the name 4 [3 (dimcthylamino)propyl]-2-isonicotinoyl-2g-1,4- benzothiazin3 (4g) -one.

9. A compound according to claim 1 having the name 3 benzoyl 1 [3-(dimethylamin0)propyl]JE-pyrido- [2,3-b} l,4]thiazin-2(3g)-one.

10. A compound according to claim 1 having the name 10 24 12. A compound according to claim 1 having the name 4 [3 (dimethylamino)propy1]-2-(a-propylcinnamoyD- 2g- 1 4-benzothiazin-3 (411) -one.

References Cited UNITED STATES PATENTS 3,471,481 10/1969 Krapcho 260-243 X JOHN M. FORD, Primary Examiner US. Cl. X.R.

260-244 R, 325, 243 R, 286 BC, 247.1, 247.2; 424-246, 248

' UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION patent 3 767 653 D d October 23, I 1973 Inventor(s) John Krapcho v It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as. shown below:

Column 21, the first formula A Y (z) I I A Y (Z) Q X i i R should X H l m A C 7 read m X 1 C=O \\A/ \N/ v a I. 1 l R 2 1 Colunn 22,- the first formula A m a should A 2 read X Talk-B Signed and sealed this 3rd day o f'December 1974.

i (SEAL) Attest: I

MCCOY M. GIBSON JR. c. MARS-HALL DANN Attesting Officer Commissioner of Patents )RM Po-wso (10-69) us'coMM-oc cove-pea U,SI GOVERNMENT PRINTING O'FICE I9! 0-30.68.

2 UNITED STATES, PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 7 67.653 Dated October 23, 1.973

Inventbfls) John Krapcho It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 28, after "atoms" insert a Column 1, line 64, after "tro" insert a Column 3, formula I-2,

N Y O X Should CH2 l m read X Y ink-B 1193 Column 4, line 70, "aminobenzenthiol" should read --amino benzenethiol--.

Column ll, line 32, "2.5" should read -22.5-.

Column 12, line 39, "thianzin" should read -thiazin'--. Column 14, example 24, after (2-hydroxyethyl)" insert -amino]ethyl chloride-. v Column 12, line 8, "60%" should read -""50/c Column 16, line 56, "pivoloyl" should read -pivaloyl-.

Signed and sealed this 11th day of June 197M. I

(SEAL) Attest:

EDWARD M.FLETCHER,JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents 

